Michael Roche

Immune-based interventions to affect an HIV cure were presented including depletion of plasmacytoid dendritic cells to reverse immune dysfunction; genome editing to remove CCR5 from T cells; use of a methyltransferase inhibitor to increase antigen presentation and clear infected cells; and anti-PD1 CAR-T cells to target SIV-infected cells.

Michelle Lee (Emory National Primate Research Centre) aimed to restore dysfunctional CD8+ T cells in SIV-infection through depletion of plasmacytoid dendritic cells using a BDCA2-specific antibody. Treatment efficiently depleted plasmacytoid dendritic cells and two of six treated animals achieved virological control after ART interruption. Priti Kumar (Yale University) demonstrated that virus like particles loaded with CRISPR machinery and coated with antibodies targeting CD7 could specifically target T cells and edit the CCR5 gene with high efficiency. In vivo CCR5 editing in a humanised mouse model of HIV infection led to ART-free virologic control. Andrea Gramatica (Weill Cornell Medicine) showed the methyltransferase inhibitor Tazemetostat could restore MHC-I expression on HIV infected cells. Treatment with Tazemetostat lead to efficient elimination of HIV-infected cells ex vivo and reduced viral loads in a humanised mouse model of HIV infection. Karsten Eichholz (Fred Hutchinson Cancer Centre) described anti-PD-1 chimeric antigen receptor T cells which rapidly depleted the PD-1+ T follicular helper cells and stopped SIV replication in the B cell follicle. However, the CAR-T cells also targeted memory CD8+ and CD4+ T cells leading to loss of immunological control, increased viral loads after ART cessation and finally development of B cell lymphoma.

Targeted depletion of plasmacytoid dendritic cells may improve anti-HIV immunity and could help induce post-treatment control. On the other hand, the PD-1 CAR-T cells are a cautionary tale that targeting specific immune cells may lead to detrimental off-target effects. The FDA approved Tazemetostat counteracts the ability of the virus to make the infected cell invisible to the immune system and is a very exciting development approach to deplete the HIV reservoir. Watch this space. Use of T cell targeting CRISPR particles shows great promise as a non-stem cell transplantation approach to remove CCR5 and affect an HIV cure.